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Molecular Pharmacology, Vol 14, 306-322, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Tentative Identification of Benzo[a]pyrene Metabolite-Nucleoside Complexes Produced in Vitro by Mouse Liver Microsomes

OLAVI PELKONEN 1, ALAN R. BOOBIS 1, HARUHIKO YAGI 1, DONALD M. JERINA 1, and DANIEL W. NEBERT 1

1 Developmental Pharmacology Branch, National Institute of Child Health and Human Development, and Section on Oxidation Mechanisms, Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014

When [3H]benzo[a]pyrene is incubated in vitro together with deproteinized salmon sperm DNA, NADPH, and mouse liver microsomes, the covalent binding of benzo[a]pyrene metabolites to DNA occurs. The metabolite-nucleoside complexes can be resolved into at least nine distinct peaks by elution of a Sephadex LH-20 column with a water-methanol gradient. These peaks are arbitrarily designated A (most polar) through I (least polar). With the use of synthetic and biologically produced metabolites, seven of nine peaks are tentatively assigned to one or more metabolites of benzo[a]pyrene. Peaks A and C are unidentified. Peaks B, D, F, and I include products of benzo[a]pyrene quinones that are further metabolized. Peak E reflects almost exclusively both the cis- and trans-7,8-diol 9,10-epoxides of benzo[a]pyrene. Peak G represents predominantly the K-region metabolite (the 4,5-oxide), interacting with one or more nucleosides. Peak H comprises reactive intermediates resulting from the further metabolism of benzo[a]pyrene phenols. The 7,8-oxide and the 9,10-oxide contribute to peaks E, F, G, and H. Benzo[a] pyrene thus may be metabolized to four different "types" of reactive intermediates capable of binding to DNA: (a) primary arene oxides, (b) diol epoxides, (c) phenols oxygenated further, and (d) quinones oxygenated further (or quinone-derived free radicals). These last three types of microsomally activated intermediates are therefore the result of two- or three-step enzymatic processes in which cytochrome P-450-mediated monooxygenations occur at least twice.

Note:
ACKNOWLEDGMENT We appreciate the expert secretarial assistance of Ms. Ingrid E. Jordan.

Submitted on July 27, 1977
Accepted on November 25, 1977






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